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Human intestinal myofibroblasts deposited collagen VI enhances adhesiveness for T cells – A novel mechanism for maintenance of intestinal inflammation

2022; Elsevier BV; Volume: 113; Linguagem: Inglês

10.1016/j.matbio.2022.09.001

1569-1802

Sinan Lin, Alessandro Musso, Jie Wang, Pranab K. Mukherjee, Gail West, Ren Mao, Ruishen Lyu, Jiannan Li, Shuai Zhao, Michael Elias, Yael Haberman, Lee A. Denson, Subra Kugathasan, Minhu Chen, Doug Czarnecki, Dina Dejanovic, Hongnga T. Le, Jyotsna Chandra, Jeremy M. Lipman, Scott R. Steele, Quang Tam Nguyen, Claudio Fiocchi, Florian Rieder,

Cancer Immunotherapy and Biomarkers

Objective: Inflammatory bowel diseases (IBD) cause chronic intestinal damage and extracellular matrix (ECM) remodeling. The ECM may play an active role in inflammation by modulating immune cell functions, including cell adhesion, but this hypothesis has not been tested in IBD. Design: Primary human intestinal myofibroblast (HIMF)-derived ECM from IBD and controls, 3D decellularized colon or ECM molecule-coated scaffolds were tested for their adhesiveness for T cells. Matrisome was analysed via proteomics. Functional integrin blockade was used to investigate the underlying mechanism. Analysis of the pediatric Crohn's disease (CD) RISK inception cohort was used to explore an altered ECM gene expression as a potential predictor for a future complicated disease course. Results: HIMF-derived ECM and 3D decellularized colonic ECM from IBD bound more T cells compared to control. Control HIMFs exposed to the pro-inflammatory cytokines Iinterleukin-1β (IL-1β) and tumor necrosis factor (TNF) increased, and to transforming growth factor-β1 (TGF-β1) decreased ECM adhesiveness to T cells. Matrisome analysis of the HIMF-derived ECM revealed collagen VI as a major culprit for differences in T cell adhesion. Collagen VI knockdown in HIMF reduced adhesion T cell as did the blockage of integrin αvβ1. Elevated gene expression of collagen VI in biopsies of pediatric CD patients was linked to risk for future stricturing disease. Conclusion: HIMF-derived ECM in IBD binds a remarkably enhanced number of T cells, which is dependent on Collagen VI and integrin αvβ1. Collagen VI expression is a risk factor for a future complicated CD course. Blocking immune cells retention may represent a novel approach to treatment in IBD.